title: Ebola virus-like particles stimulate type I interferons and proinflammatory cytokine expression through the toll-like receptor and interferon signaling pathways.
abstract: Ebola viruses (EBOV) can cause severe hemorrhagic disease with high case fatality rates. Currently, no vaccines or therapeutics are approved for use in humans. Ebola virus-like particles (eVLP) comprising of virus protein (VP40), glycoprotein, and nucleoprotein protect rodents and nonhuman primates from lethal EBOV infection, representing as a candidate vaccine for EBOV infection. Previous reports have shown that eVLP stimulate the expression of proinflammatory cytokines in dendritic cells (DCs) and macrophages (MΦs) in vitro. However, the molecular mechanisms and signaling pathways through which eVLP induce innate immune responses remain obscure. In this study, we show that eVLP stimulate not only the expression of proinflammatory cytokines but also the expression of type I interferons (IFNs) and IFN-stimulated genes (ISGs) in murine bone marrow-derived DCs (BMDCs) and MΦs. Our data indicate that eVLP trigger host responses through toll-like receptor (TLR) pathway utilizing 2 distinct adaptors, MyD88 and TRIF. More interestingly, eVLP activated the IFN signaling pathway by inducing a set of potent antiviral ISGs. Last, eVLP and synthetic adjuvants, Poly I:C and CpG DNA, cooperatively increased the expression of cytokines and ISGs. Further supporting this synergy, eVLP when administered together with Poly I:C conferred mice enhanced protection against EBOV infection. These results indicate that eVLP stimulate early innate immune responses through TLR and type I IFN signaling pathways to protect the host from EBOV infection.
authors.affiliation: 1 Program in Genomics of Differentiation, National Institute of Child Health and Human Development , National Institutes of Health, Bethesda, Maryland.
authors.forename: Natarajan
authors.initials: N
authors.lastname: Ayithan
authors.forename: Steven B
authors.initials: SB
authors.lastname: Bradfute
authors.forename: Scott M
authors.initials: SM
authors.lastname: Anthony
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Stuthman
authors.forename: John M
authors.initials: JM
authors.lastname: Dye
authors.forename: Sina
authors.initials: S
authors.lastname: Bavari
authors.forename: Mike
authors.initials: M
authors.lastname: Bray
authors.forename: Keiko
authors.initials: K
authors.lastname: Ozato
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology; D029043:Ebolavirus / Q000276:immunology*; D019142:Hemorrhagic Fever, Ebola / Q000276:immunology* / Q000517:prevention & control; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D018836:Inflammation Mediators / Q000378:metabolism; D007370:Interferon Type I / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D011070:Poly I-C / Q000008:administration & dosage; D011323:Primates; D051381:Rats; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism; D058425:Vaccines, Virus-Like Particle; D014771:Virion / Q000276:immunology*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016207:Cytokines; D018836:Inflammation Mediators; D007370:Interferon Type I; D053594:Myeloid Differentiation Factor 88; D011070:Poly I-C; D053633:Receptor, Interferon alpha-beta; D051193:Toll-Like Receptors; D058425:Vaccines, Virus-Like Particle; C508032:Ifnar1 protein, mouse; C476286:Ticam1 protein, mouse